1. Field of the Invention
The present invention relates to specimen or sample inspection systems and more particularly to systems in which human operators inspect a substantial number of individual specimens to locate a particular subset such as xe2x80x9csuspiciousxe2x80x9d or irregular specimens. As used herein, the term xe2x80x9cspecimenxe2x80x9d is not necessarily limited to a medical or biological specimen but may more generally extend to any sample item or portion of a group as a whole.
2. Description of Related Art
The present invention may find particular use in a variety of contexts such as, for example, examining histological specimens (i.e., tissue-based as in anatomic pathology), examining cytological specimens (i.e., cellular samples (such as those taken from body cavity fluids, voided urine, sputum, and gynecological tract) as analyzed by cytotechnologists and cytopathologists, cytogeneticists, hematologists, neuroscientists, etc.), examining silicon wafers in an integrated circuit manufacturing process, and other materials inspection processes. In a typical scenario, a human inspector must inspect and analyze a substantial number of specimens each day to determine whether the specimens deviate from some predetermined norm. Abnormal specimens are identified and are subject to further, more detailed review. The subsequent, more detailed review may require a reviewer with additional expertise, such as a pathologist in the case of the Pap test. In a usual case, most of the specimens are considered xe2x80x9cnormal,xe2x80x9d or xe2x80x9cwithin normal limits,xe2x80x9d and therefore need not be subjected to additional scrutiny. Depending on the detail and scope of this inspection and analysis, this additional scrutiny can unfortunately be a very slow, painstaking and costly process.
For purposes of illustration, the present invention will be described in the context of cytological specimen analysis, such as cervical Pap smear analysis. Pap smears, which are routinely taken from women, facilitate the detection of pre-cancerous changes and/or the early stages of cancer, thus reducing the chances of any cancer or related abnormal condition from spreading or advancing with the resultant negative impact on the prognosis for the patient. A Pap smear is prepared by first collecting a vaginal, cervical and endocervical tissue sample from a patient. The sample is then fixed to a slide, for instance by alcohol fixation, and appropriately stained to enable microscopic analysis.
It will be understood, however, that the conventional Pap smear process is limited, because it produces large numbers of cells (50,000 to 300,000 cells per Pap smear, typically) that are often obscured by inflammatory or other materials that make accurate and sensitive diagnoses more difficult in some cases. The Pap smear process is also limited because it deposits the cells in a spatially non-uniform manner that is difficult and time-consuming to analyze visually, as shown, for instance, in FIG. 8.
As an alternative to a Pap smear, the specimen may take the form of a liquid-based or monolayer preparation, prepared with instruments manufactured, for instance, by AutoCyte or Cytyc. One method of preparing such a specimen depends upon centrifugation to separate cells before deposition onto a glass microscope slide, for example. Another method relies upon physical filtration of a specimen through a filter with a controlled pore-size distribution. An example of the latter approach is the Cytyc ThinPrep(copyright) instrument and process.
The Cytyc ThinPrep(copyright) sample preparation generally comprises straining a sample through a filter having pores smaller than the average sample cell diameter but sufficiently large to allow passage of cellular and other debris. In one embodiment, the pore diameter is about 40-50 micrometers. The filter preferably has no rough edges or other features that would rupture the sample cells. Upon filtration, sample cells remain on the filter surface while the debris passes through, resulting in a filter surface enriched in sample cells and depleted in debris. The filter surface is next pressed onto a microscope slide to transfer the sample cells from the filter surface to the slide. This results in the slide having a monolayer of cells and, by employing a filter having a smaller area than the slide, a higher concentration of sample cells, substantially free of cellular and other debris that could interfere with a cytotechnologist""s analysis of a slide. The Cytyc ThinPrep(copyright) sample preparation thus provides a more spatially uniform distribution of cells within a cellular disk (CD), as shown, for instance, in FIG. 9.
In practice, after the specimen is prepared, the slide is screened by a highly skilled technician (xe2x80x9ccytotechnologistxe2x80x9d), in an effort to identify possible cellular abnormalities in the specimen and to determine the specimen adequacy. The cytotechnologist generates notes regarding each specimen deemed to have possible abnormalities. The cytotechnologist then provides the specimen slide, together with notes of his or her findings, to an expert pathologist (i.e., specialized physician) for further review and final specimen diagnosis.
To screen a Pap smear specimen, the cytotechnologist generally views the Pap smear slide containing the Pap smear through a microscope to detect the presence of cancer cells or cells exhibiting other abnormal conditions. Because a cancerous cell may appear in only one of thousands of locations in an otherwise normal-appearing specimen, however, the cytotechnologist must generally examine every area of the slide in order to make a valid (i.e., accurate) determination. Further, many portions of the specimen slide may contain no cells at all, but the cytotechnologist must examine even those areas to at least determine the absence of pertinent (i.e., diagnostically significant) material. Of course, this process of thoroughly screening a specimen for the presence of cancerous or abnormal cells is often laborious, error-prone and costly. Still, cytotechnologists have been known to examine more than 20,000 slides annually in an effort to classify specimens as within normal limits and to identify abnormalities and enable pathologists to diagnose Pap smear specimens. In many cases, this specimen review rate is driven in part by financial concerns such as competition based on the number of specimens analyzed.
Based on the cytotechnologist""s primary review (i.e., screening) of the specimen, the cytotechnologist determines either that the specimen contains suspicious material such as precancerous or cancer cells, or that the specimen is apparently within normal limits. Typically, statistically speaking, xe2x80x9csuspiciousxe2x80x9d and xe2x80x9cabnormalxe2x80x9d specimens may account for approximately 5% to 10% of Pap smears in the United States, in laboratories that are screening asymptomate women. The remaining statistical 95% to 90% of the cases in turn are classified as apparently normal.
If a specimen contains even a single well preserved and well-stained cancer cell out of tens or hundreds of thousands of cells, the cytotechnologist should find the specimen to be suspicious, or atypical or abnormal. Failure to properly identify a specimen as abnormal during this screening process may be disastrous, as it may leave a cancer undetected and untreated and may ultimately lead to the death of the patient.
The cytotechnologist forwards all xe2x80x9csuspicious,xe2x80x9d or xe2x80x9catypicalxe2x80x9d or xe2x80x9cabnormal,xe2x80x9d specimens to a pathologist for detailed review and final diagnosis and xe2x80x9csign-outxe2x80x9d in light of the cytotechnologist""s notes and findings. One of the pathologist""s goals is to analyze the specimen at issue and determine based on medical expertise whether the specimen contains cancerous or pre-cancerous cells. In doing so, the pathologist must strive to minimize both false negative diagnoses and false positive diagnoses, as false negative diagnoses could leave cancer undetected, while false positive diagnoses could result in unnecessary or inappropriate, harmful and costly cancer treatment such as chemotherapy or the like.
Most of the specimens that the cytotechnologist deems to be xe2x80x9capparently normalxe2x80x9d are classified as within normal limits, and the analysis of those specimens is completed. However, to minimize the possibility of false negatives in the screening process and to identify cytotechnologists that may have screening quality performance problems, at least some of those specimens should be subject to a secondary screening, or xe2x80x9cre-screening,xe2x80x9d by a cytotechnologist. In the United States, at least 10% of these xe2x80x9capparently normalxe2x80x9d specimens must be randomly selected and re-screened for quality assurance by a different cytotechnologist.
In addition, to further minimize false negatives during the Pap smear screening process, cytotechnologists must spend sufficient time screening each specimen slide. For this reason, legal regulations in some states in America restrict individual cytotechnologists to screening no more than 100 Pap smear slides in a single day. Other states provide even stricter limitations, such as a maximum of 80 slides per day. Assuming an average 7 hour work day, these regulations would have a typical cytotechnologist screening and classifying an average Pap smear slide in no more than 4.20 to 5.25 minutes.
Notwithstanding these maximum limitations, the average number of Pap smear slides screened per day by cytotechnologists in the United States is on the order of only 50 to 60, corresponding to cytotechnologists typically spending less than 7 to 8 minutes reviewing each slide in order to carefully determine whether any abnormal cells are present. Of course, as cytotechnologists spend more time screening each slide, they will theoretically make fewer false negative errors. At the same time, however, as cytotechnologists spend more time screening each slide, they will screen fewer slides each day, and the labor and cost of specimen screening will consequently rise.
A need therefore exists for a more efficient specimen screening system that minimizes the presence of false negative specimen classification errors while reducing the time required to analyze specimens accurately and to compile useful information about suspicious, atypical, or abnormal specimens for reference by diagnostic experts.
3. Background References
European Patent Application Publication No. 0 647 844 A2, to Hoffman-La Roche, describes a system for expedited handling of cytology samples, involving interaction between a cytotechnologist and automated machine analysis. A system automatically analyzes cells in the specimen and makes a diagnosis based on this analysis. The system then generates a gallery of cells and displays the gallery to a cytologist. The cytologist reviews the gallery, makes an independent determination whether any of the cells are abnormal (without yet knowing the system""s diagnosis), and inputs the determination into the system. The system then compares its review with the cytologist""s review. If both believe the slide to be normal, a xe2x80x9cnormalxe2x80x9d diagnosis is reported; if either find abnormalities, the slide is forwarded to another cytologist for full review. Alternatively, if the cytologist finds the slide to be normal but the computer does not, the gallery can be reviewed by a supervisor or re-reviewed by the cytologist.
U.S. Pat. No. 5,625,705, to Recht, describes a method for classifying objects in a specimen as likely to be premalignant or malignant cells, based on an intensity texture analysis. According to Recht, an automated microscope system first scans a specimen slide at low resolution, an image processor identifies areas that may contain biological matter, and the image of the area is stored together with an indication of its focal plane. The system then scans the specimen at a higher resolution and conducts a gray scale analysis of each identified area to determine (e.g., by size, gray scale density or surface intensity texture characteristics) if the area contains a premalignant or malignant cell. If so, an area of pixels encompassing the cell is generated, and the system re-scans the area at a high resolution to produce a high resolution color image tile (xe2x80x9cnet imagexe2x80x9d) of the cell and its surroundings. For each such tile, the system then determines a likelihood (xe2x80x9cnet valuexe2x80x9d) that the object is a premalignant or malignant cell. Finally, the system generates and displays an 8xc3x978 summary screen of the tiles having the highest net values, which a cytotechnician can scan in search of an object having attributes of the cell type for which classification is being performed.
International Patent Application Publication No. WO 96/03709 A1, to Neuromedical Systems, Inc., describes a method for facilitating review of a selected specimen or area of interest with a microscope. An automated microscope scans a specimen image, and an image processor morphologically filters the image to identify possibly malignant or premalignant cells. After additional processing, images and their coordinates are stored for display on a monitor. The 64 highest ranked cells are then presented to a cytotechnician in an 8xc3x978 matrix, or other sequence (e.g., simultaneously or separately) or arrangement such as four screens of a 4xc3x974 matrix of tiles. In order to ensure that the cytotechnician looks at each of the tiles, the system then requires the cytotechnician to position a cursor on each image for a set period of time determined to be sufficiently long for inspection of a tile.
The present invention provides improved efficiency in specimen analysis by better managing information associated with the specimen at issue. In turn, the invention recognizes that a skilled technician or technologist need not serially review every area of a specimen on a glass microscope slide or other substrate to locate one or more areas that are suspicious or abnormal, as long as the technician is provided with useful information about the specimen. Further, the invention recognizes that useful information may arise from information derived before the screening process by manual or automated techniques, or from the screening process itself, even if not expressly noted by the screening technician.
The present invention introduces a preview stage into the specimen screening process. The preview stage enables the technician to conveniently review information pertinent to the specimen at issue. A preview processor collects, measures, assembles, stores, communicates, displays and manages a variety of useful information about the specimen for quick analysis by the technician. In the context of Pap smear screening, this information may include, for example, aspects of the patient""s medical history and medical risk factors, information pertinent to the preparation of the specimen, information about other tests conducted on the specimen from samples derived from aliquots of the same specimen, and discrete images of the most suspect cells on the slide from the specimen. The technician can flag (i.e., electronically mark) any of the information that may bear on whether the specimen at issue is abnormal. In addition, the technician may view other related information to place the specimen in context, such as, for instance, comparing the specimen with other known specimens having similar characteristics. Such comparison may be visually based upon cell images, or may be based on a graphical plot, numerical data or textual descriptions.
Provided with this preview information, the technician can quickly form an educated opinion as to whether the specimen at issue is likely to be normal or is likely to be suspect. The technician then conducts an actual screening of the specimen, for instance, through an automated microscope keyed to an established routing function. Beneficially, if the technician has already determined from the preview stage that the specimen is likely to be normal, for instance, by finding no information suggesting the presence of abnormalities, either from prior data or from specific specimen-derived information, then the technician may accelerate the specimen-screening process and may quickly screen the specimen in less than currently average time. Alternatively, if the technician has determined that the specimen is likely to be of interest, for instance, by having noted or flagged suspicious cells or other significant information, then the technician may appropriately spend more than an average amount of time screening the specimen. The previewed information can also be used to xe2x80x9cdrivexe2x80x9d the cytotechnologist to suspicious areas on the slide before the routine screening function begins.
Additionally, as the technician examines and flags pertinent information associated with the specimen at issue during the preview stage, this information may conveniently be stored in an electronic record together with the technician""s notes, for subsequent review by a diagnosing expert. This record may be associated with the specimen by a bar code or other identifying indicia. As the expert may also be provided with the coordinates identifying specific regions of the specimen referenced by the technician, the expert may beneficially associate the information flagged by the technician with specifically identified regions of the specimen.
In addition to including expressly flagged information in the record associated with each specimen, the invention may further include in the record useful information about the actual screening process automatically flagged by a computer-aided instrument that monitors the screener""s behavior. For instance, in the event the technician spends a significant amount of time reviewing one particular area of the specimen, the invention may automatically include an indication in the record that the particular area may be of interest. In this way, even if the technician fails to expressly flag a region or expressly note the possible significance of a region of the specimen, the reviewing expert may be provided with useful information or hints about the region.
It is thus an object of the present invention to provide a prescreening system for specimen analysis. It is a further object of the present invention to provide a system for channeling a screening technician""s interest and attention on specimens most likely to be suspect as well as the most suspect information about, and areas of, those specimens. Still further, it is an object of the present invention to provide a system for automatically compiling useful specimen-analysis information for subsequent review, based on information flagged by a screening technician and further based on the behavior of the screening technician. Yet further, an object of the present invention is to provide a specimen screening station that enables accurate, precise and robust analysis. Additionally, an object of the present invention is to provide a human screener with an apparatus and method to reduce screening times significantly for within normal-limit specimens (i.e., the most prevalent cases) without sacrificing diagnostic accuracy.
These, as well as other objects and advantages of the present invention will become readily apparent to those skilled in the art by reading the following detailed description, with appropriate reference to the accompanying drawings.